HIV-1 buds off cell membranes and incorporates host proteins in its envelope. In this proposal, we address the impact these host proteins have on HIV immunity. We will test the hypothesis that during HIV infection, antibodies are made against epitopes formed partly by host proteins and partly by viral Env glycoproteins and that such antibodies have broad anti-viral activity. Thus, we propose the very novel concept that chimeric antigens, consisting of a stable or transient interface between host and viral components, are a feature of viral immunity. If our hypothesis is correct, immunogens could be made by combining viral proteins with conserved host proteins, thereby allowing a high proportion of conserved determinants. In addition, since chimeric antigens are likely to be conformational, unique immunogens based on conserved structures derived from host/virus interfaces could be constructed. We will accomplish the following specific aims: 1) Screen mAbs for binding to chimeric antigens. We will screen mAbs (from HIV-infected subjects) against virus-like particles (VLPs) or Env-expressing cells with or without host proteins known to occur on virion surfaces. Expression of host proteins will be regulated by RNA interference (RNAi). mAbs binding only to VLPs or cells expressing both Env and a host protein of interest will be evaluated further; 2) Determine the antiviral function of mAbs directed against chimeric antigens. Antibodies will be tested for neutralization and antibody-dependent cell-mediated virus inhibition against a panel of HIV-1 strains. Since we will screen as many as 1,000 mAbs and consider at least 20 host proteins as partners with Env in forming epitopes, we will have an excellent chance of finding chimeric antigens should they exist. Moreover, the extent of our screening will provide confidence in a negative result. Thus, our methods are designed to fully explore the hypothesis that antibodies against chimeric antigens occur during HIV infection, and we will gain strong evidence of their presence or absence. If successful, our research will result in a paradigm shift away from the concept that anti- viral antibody responses are always directed against uniquely viral epitopes and toward the decidedly new concept of epitopes made from virus plus host. Moreover, our novel concept of chimeric antigens may yield new, broadly anti-viral mAbs and novel immunogens that elicit broadly anti-viral responses. Discovering chimeric antigens could have a profound impact on HIV prevention by overcoming seemingly intractable obstacles to an effective vaccine. A major obstacle to the development of an HIV vaccine is the lack of an immunogen that elicits broadly anti- viral antibody responses. We propose an exceptionally novel approach to discover such immunogens. If successful, this research may lead directly to a vaccine that prevents HIV infection.